Benzocycloheptapyrans, compositions, and method of treatment

ABSTRACT

Octahydro and hexahydrobenzo[b]cyclohepta[d]pyrans having the general formula ##STR1## wherein R 1  is hydrogen or alkanoyl, R 2  is alkyl or alkenyl, R 3  is hydrogen or alkyl, and Z is a two carbon alkylene chain which is substituted or unsubstituted and saturated or unsaturated are provided. Pharmaceutical compositions containing such benzocycloheptapyrans, and a method of treating hypertension are disclosed.

BACKGROUND OF THE INVENTION

The very potent biological activities attributable to compoundsstructurally related to the active ingredients of Cannabis sativa L. hasgenerated a great deal of interest and research during the past severalyears. Numerous chemical modifications has led to the discovery ofextremely potent compounds of the cannabinoid family which areclinically useful. U.S. Pat. Nos. 3,928,598, 3,944,673 and 3,953,603describe several hexahydrodibenzo[b,d]pyrans which are particularlyuseful in the treatment of anxiety, pain and depression. Novel methodsof preparation of such compounds has been summarized by Archer et al. inJ. Org. Chem., 42, 2277 (1977).

While a great deal of synthetic chemistry has been devoted to themodification of the substitution patterns of pharmacologically activedibenzo[b,d]pyrans, very little chemical research has been directed tostructural modification of the basic tricyclic nucleus of suchcompounds. The synthesis of certain B-ring homocannabinoid derivatives,i.e. dibenz[b,d]oxepins, recently has been disclosed by Matsumoto et.al., J. Med. Chem., 20, 25(1977) and by Freedman, U.S. Pat. No.3,859,306. Similarly, benzopyran-type compounds having a 5 or 6-memberedC-ring have been described in U.S. Pat. Nos. 2,972,880, 4,051,152,4,007,207 and 4,025,630.

It is an object of this invention to provide 6,6,7-tricyclic compoundswhich are structurally similar to dibenzo[b,d]pyrans and which areextremely active pharmacologically while at the same time not causingsome of the deleterious side effects often observed with conventionalmarijuana-like compounds.

SUMMARY OF THE INVENTION

The invention relates to compositions of matter characterized astricyclic compounds wherein a 6-membered aromatic ring is fused to theb-side of a pyran ring, and a cycloheptane ring is fused to the d-sideof such pyran. More particularly, the invention is directed to octahydroand hexahydrobenzo[b]cyclohepta[d]pyrans defined by the generalstructural formula ##STR2## wherein: R¹ is hydrogen or C₁₋₄ alkanoyl;

R² is C₅ -C₁₀ alkyl or C₅ -C₁₀ alkenyl;

R³ is hydrogen or methyl; and

Z is selected from the group consisting of ##STR3## in which: R⁴ ishydrogen or C₁ -C₄ alkoxycarbonyl;

R⁵ is hydrogen or C₁ -C₄ alkyl; and

R⁶ is hydrogen or hydroxy.

A preferred group of compounds are defined by the above formula whereinR¹ is hydrogen and R³ is methyl.

Another preferred group of compounds are those according to the aboveformula wherein Z is selected from ##STR4## R⁵ is hydrogen or methyl,and R⁶ is hydroxy.

A particularly preferred group of benzocycloheptapyrans contemplated bythis invention are those of the above formula wherein

R¹ is hydrogen,

R² is alkyl,

R³ is methyl, and

Z is selected from ##STR5## wherein: R⁵ is hydrogen or methyl.

This invention additionally comprehends pharmaceutical formulationscomprising as active ingredient at least one of thebenzocycloheptapyrans of the above general formula in combination with asuitable diluent or carrier therefor. Such formulations are useful inthe treatment of anxiety, pain, depression, glaucoma and hypertension.

A preferred formulation according to this invention comprises a compoundof the above general formula wherein

R¹ is hydrogen,

R² is alkyl,

R³ is methyl and

Z is selected from ##STR6## wherein: R⁵ is hydrogen or methyl and

R⁶ is hydrogen or hydroxy, in combination with a pharmaceutical carriertherefor.

Yet another embodiment of this invention is a method of treatinghypertension which comprises administering to a subject suffering fromhypertension and in need of treatment or to a subject suspended ofhaving incipient hypertension an amount sufficient to lower bloodpressure of a benzocycloheptapyran having the above general formula.

A preferred method of treatment according to this invention comprisesadministering a hypotensively effective dose of a compound having theabove formula wherein:

R¹ is hydrogen

R² is alkyl,

R³ is methyl, and

Z is selected from the group consisting of ##STR7## wherein: R⁵ ishydrogen or methyl and

R⁶ is hydrogen or hydroxy.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula defining the benzocycloheptapyrans providedby this invention, R¹ is defined as hydrogen or C₁ -C₄ alkanoyl. Theterm "C₁ -C₄ alkanoyl" as used herein refers to an acyl residue of acarboxylic acid having from 1 to 4 carbon atoms. Examples of such C₁ -C₄alkanoyl groups include formyl, acetyl, propionyl, n-butyryl, andisobutyryl.

R² in the above formula is defined as a C₅ -C₁₀ alkyl group or as a C₅-C₁₀ alkenyl group. Such terms take on the meaning assigned to themthroughout the chemical art relating to dibenzopyrans. Examples of "C₅-C₁₀ alkyl" groups thus include both straight and branched chain alkylgroups such as n-pentyl, n-hexyl, n-heptyl, 1,1-dimethylheptyl,1,2-dimethylheptyl, 1-ethyloctyl, 1,1-dimethyloctyl,1,2,3-trimethylheptyl, 1-propylhexyl, isooctyl, n-decyl, and the like.The term "C₅ -C₁₀ alkenyl" similarly refers to straight and branchedalkenyl chains known in the art, examples of which include 2-pentenyl,3-hexenyl, 5-heptenyl, 1,1-dimethyl-2-heptenyl, 1,2-dimethyl-1-heptenyl,2,3-dimethyl-2-heptenyl, 1-ethyl-2-octenyl, 2-ethyl-1-heptenyl,2-decenyl, 1-nonenyl, 1-methyl-1-nonenyl, and related alkenyl groups.

In the above structural definitions for the variable referred to as Z,R⁴ defines hydrogen or a C₁ -C₄ alkoxycarbonyl moiety. Examples of C₁-C₄ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl and tert.-butoxycarbonyl. R⁵ in the above formulaedefines, in addition to hydrogen, a C₁ -C₄ alkyl group such as methyl,ethyl, n-propyl, iso-butyl or the like.

The compounds provided by this invention will be named throughout thisdisclosure by referring to the following general formula bearing thenumbering system as shown: ##STR8## wherein Z has the above-definedmeaning, and wherein the two ring carbon atoms defined by Z are numberedin order as 9 and 10 respectively as shown in the above part formulaedefining Z. It will be noted by those skilled in the art that since thering juncture, defined in the above formula as the 6a,11a positions, istotally saturated, several optical isomers are possible because of theasymmetric orientations occuring at those centers. When naming suchoptical isomers, the following conventions will be observed: when thehydrogen atom attached at the 6a-position is oriented on the side of themolecule opposite to the hydrogen atom attached at the 11a-position, theresulting molecule is said to have a "trans" stereochemicalconfiguration, and is more specifically designated as a 6a,11a-transracemate. It should be further noted that two optical isomers of thetrans configuration are possible. For example, the absolutestereochemical configuration of the 6a-hydrogen atom can be below theplane of the ring, in which case it is referred to as a 6aS-hydrogenatom. Similarly, the 11a-hydrogen atom can be above the plane of themolecule, in which case it is referred to as an 11aS-hydrogen atom.Conversely, the 6a-hydrogen can be above the plane of the ring, and isdesignated a 6aR hydrogen atom, and the 11a-hydrogen can be orientedbelow the plane and designated as an 11aR hydrogen atom. The two6a,11a-trans isomers form a racemic dl or ± pair of isomers. Similarly,both the 6a and 11a hydrogen atoms can be oriented on the same side ofthe plane of the molecule, in which case the compound is referred to asa "cis" racemate, and more specifically as a 6a,11a-cis racemate. Whenboth the 6a-hydrogen and the 11a-hydrogen atoms are oriented above theplane of the molecule, the compound is more accurately referred to as a6aR,11aR-cis isomer, while if both hydrogen atoms are oriented below theplane of the molecule, the particular isomer is defined as the6aS,11aR-cis isomer, and the two cis isomers together form a racemic dlor (±) pair.

The absolute stereochemical configuration of the 6a and 11a positions ofthe benzocycloheptapyrans of this invention will not hereinafter bedesignated. Rather, it is to be understood that the designation "cis"includes not only the individual mirror image isomers at the 6a and 11apositions in compounds having the above general formula, but also the dlor (±)-mixture of such mirror image cis isomers. Similarly, the term"trans" will include each separate 6aS,11aS isomer and its 6aR, 11aRmirror image, as well as the racemic (±)-mixture of such trans isomers.The particular stereochemical configuration occuring at the 6a and 11aposition of the compounds of this invention will be determined by thestereochemical configuration of the starting material from which suchcompounds are derived, since the stereochemical integrity of thestarting material is maintained throughout the synthetic procedures usedto prepare the compounds of this invention. Furthermore, since one ofthe separate optically active isomers may have little or nopharmacological activity, it is preferred to utilize racemic (±)mixtures of isomers as active drugs rather than to prepare and use thecorresponding optically active individual isomers. The (±)-6a,11a-transisomers appear, in general, to be somewhat more active biologically bythan the corresponding (±)-6a,11a-cis isomers. It is therefore desirableto prepare and use the (±)-trans-benzo[b]cyclohepta[d]pyrans of thisinvention. Accordingly such compounds are preferred as activeingredients in the formulations and processes of this invention.

In naming the compounds of this invention, the stereochemical nature ofthe molecule is first indicated; eg. (±)-trans, (±)-cis, etc. Allcompounds will be named as benzo[b]cyclohepta[d]pyrans, with the varioussubstituent groups named in order of location on the ring system. As anexample, a racemic compound having the above formula wherein R¹ ishydrogen, R² is n-pentyl, R³ is methyl and Z is ##STR9## wherein R⁵ andR⁶ both are hydrogen, and wherein the hydrogen atoms at the 6a and 11apositions are cis to one another, is named as follows:(±)-6a,11a-cis-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran.

The benzo[b]cyclohepta[d]pyrans provided by this invention are derivedfrom hexahydrodibenzo[b,d]pyran-9-ones. Such starting materials arereadily available by various synthetic schemes disclosed in the chemicalart. Both (±)-6a,10a-cis and(±)-6a,10a-trans-hexahydrodibenzo[b,d]pyran-9-ones are available by themethods described in U.S. Pat. Nos. 3,953,603 and 3,507,885. Opticallyactive cis and trans pyranone derivatives can be prepared by the methodsdescribed by Archer et al. J. Org. Chem., 42, 2277 (1977).

The compounds of this invention are accordingly prepared as follows: a1-hydroxy-3-alkyl(or3-alkenyl)-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran-9one isreacted with a C₁ -C₄ alkyl ester of diazoacetic acid in the presence ofa catalyst such as triethyloxonium tetrafluoroborate or borontrifluoride. The diazoacetic acid ester interacts with the 9-keto groupof the dibenzopyranone. The net result of such interaction is theevolution of nitrogen and concomitant ring enlargement to provide amixture of β-keto esters, which are compounds having the above generalformula wherein R¹ is hydrogen, R² is alkyl or alkenyl, R³ is hydrogenor methyl, and Z is selected from the group consisting of ##STR10##wherein R⁴ is C₁ -C₄ alkoxycarbonyl. The reaction typically is carriedout by mixing the C₁ -C₄ alkyl diazoacetate, the catalyst, eithertriethyloxonium tetrafluoroborate or boron trifluoride, and thehexahydro-dibenzo[b,d]pyran-9-one in a suitable unreactive solvent suchas dichloromethane, diethyl ether, benzene, toluene, or the like. Theresulting mixture is stirred at a temperature of about 0° C. for aperiod of time ranging from about ten minutes to about three hours. Thereactants are conveniently utilized in approximately equimolarquantities; however, an excess of either may be used without materiallyaffecting the yield of benzocycloheptapyran which is formed. Preferably,the alkyl diazoacetate is reacted with about a two to three molar excessof a 1 to 3 molar mixture of the dibenzopyranone and triethyloxoniumtetrafluoroborate. The product of such reaction is readily isolated bysimply washing the reaction mixture with an aqueous base such as dilutesodium hydroxide or dilute sodium bicarbonate. Separation of the organiclayer followed by removal of the solvent by evaporation under reducedpressure then provides, as products of the reaction, a mixture ofgeometrical isomers at the 9 and 10-positions. In particular, suchreaction provides a mixture of 9-oxo-10-alkoxycarbonyl and9-alkoxycarbonyl-10-oxo-octahydrobenzo[b]cyclohepta[d]pyrans. Suchmixture is readily separated into its respective components by routinepurification procedures such as liquid-solid chromatography, fractionalcrystallization, high pressure liquid chromatography and the like.

The 9-oxo-10-alkoxycarbonyl and9-alkoxycarbonyl-10-oxo-octahydrobenzo[b]cyclohepta[d]pyrans thusprepared are useful as pharmacological agents, but are preferablyutilized as intermediates in the synthesis of other compounds of thisinvention. Such compounds can, for example, be hydrolyzed to provide thecorresponding β-keto acid, which acid is readily decarboxylate atelevated temperatures. The hydrolysis of the alkoxycarbonyl derivativescan be effected in normal fashion, for instance by reaction with an acidsuch as hydrochloric acid or a base such as sodium hydroxide. Typically,a 9-oxo-10-alkoxycarbonyl or9-alkoxycarbonyl-10-oxo-octahydrobenzo[b]cyclohepta[d]pyran is dissolvedin an acid suchas formic acid, acetic acid, sulfuric acid, hydrochloricacid, or a mixture of any of such acids, and heated to a temperature ofabout 50° to about 200° C. for a period of time of about one to threehours. The alkoxycarbonyl moiety is converted to a hydroxycarbonylmoiety, which immedately expels carbon dioxide under such reactionconditions to provide the corresponding 9-oxo or10-oxo-octahydrobenzo[b]cyclohepta[d]pyran. Such compounds have theabove general formula wherein R¹ is hydrogen, R² is alkyl or alkenyl, R³is hydrogen or methyl, and Z is selected from ##STR11## The 9-oxo or10-oxo derivative thus formed can be isolated by simply extracting theacidic or basic reaction mixture with a suitable water immiscibleorganic solvent such as diethyl ether, dichloromethane, benzene, or thelike. Removal of the organic solvent then provides the corresponding9-oxo or 10-oxo-octahydrobenzo[b]cyclohepta[d]pyran, which compound canbe further purified if desired by standard methods such ascrystallization or chromatography.

The 9-oxo and 10-oxo derivatives thus formed, in addition to possessinguseful pharmacological activity, are valuable intermediates and can inturn be reduced to provide the 9-hydroxy and10-hydroxy-octahydrobenzo[b]cyclohepta[d]pyrans of the invention, oralternatively they can be reacted with a C₁ -C₄ alkyl Grignard reagentto afford the corresponding 9-alkyl-9-hydroxy and10-alkyl-10-hydroxyoctahydrobenzo[b]cyclohepta[d]pyrans of thisinvention.

The reduction of a 9-oxo or a 10-oxo-octahydrobenzo[b]cyclohepta[d]pyranto afford the corresponding 9-hydroxy or 10-hydroxy derivative can becarried out by reaction with any of a number of routinely used reducingagents. Commonly used reducing agents include organometallics and metalhydrides such as sodium borohydride, diborane, diisoamylborane, lithiumaluminum hydride and lithium aluminum trimethoxy hydride. Catalytichydrogenation can also be employed utilizing catalysts such as palladiumand platinum. The reduction reaction, whether chemical or catalytic,generally is carried out in a solvent such as ethanol, diethyl ether,benzene, or the like, and typcially is complete within two to abouttwenty-four hours. As a typical example, a 10-oxo derivative such as1-hydroxy-3-(2-hexenyl)-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyrancan be reacted with about a one to ten molar excess of sodiumborohydride in a solvent such as ethanol. The reaction is carried out ata temperature of about 20° to 50° C., and is complete within abouttwelve hours. The product is recovered by simply washing the reactionmixture with an aqueous acid such as dilute hydrochloric acid,separating the organic layer and then removing the solvent therefrom.The product so formed is a racemic mixture of 10-hydroxybenzocycloheptapyran derivatives, wherein the hydroxy group attached tothe C-ring is oriented in the α stereochemical position as well as inthe β position. Such mixtures can be separated if desired and furtherpurified by standard methods such as chromatography.

Both the 9-hydroxy and the10-hydroxy-octahydrobenzo[b]cyclohepta[d]pyrans of this invention arevaluable pharmacological agents. Such compounds additionally serve asintermediates as described hereinafter.

As previously pointed out, the 9-oxo and10oxo-octahydrobenzocycloheptapyrans of this invention can be reactedwith C₁ -C₄ alkyl Grignard reagents to provide the corresponding9-alkyl-9-hydroxy or10-alkyl-10-hydroxy-octahydrobenzo[b]cyclohepta[d]pyrans of thisinvention. Such compounds have the above general formula wherein R¹ ishydroxy and Z is selected from ##STR12## wherein R⁵ is C₁ -C₄ alkyl andR⁶ is hydroxy. Commonly used Grignard reagents include methyl magnesiumbromide, ethyl magnesium bromide, isobutyl magnesium bromide, and thelike. The reaction is carried out according to standard Grignardreaction conditions. For instance, a 9-oxo derivative such as6a,11a-cis-1-hydroxy-3-n-octyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyrancan be reacted with an excess of a Grignard reagent, such as a two molarexcess of n-propyl magnesium bromide. The reaction normally is carriedout in an inert solvent such as diethyl ether, generally at atemperature of about 0° to 50° C., and routinely is complete after aboutten to twenty hours. The product can be isolated by simply washing thereaction mixture with an aqueous acid, separating the organic layer andthen evaporating the reaction solvent therefrom. The product of suchreaction is, in the illustration,6a,11a-cis-1-hydroxy-3-n-octyl-9-hydroxy-9-n-propyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran.It should be recognized that such product is a mixture of isomers at the9-position, since in one case the 9-hydroxy group can be oriented belowthe plane of the ring (i.e. α) and the 9-alkyl group can be orientedabove the plane of the ring (i.e. β), while in another case the9-hydroxy group can be oriented above and the 9-alkyl group orientedbelow the plane of the ring. Such mixtures can be separated bychromatography if desired, or can be utilized as a mixture of isomersboth pharmacologically and as intermediates in the synthesis of othercompounds of the invention.

Any of the 9-alkyl-9-hydroxy and 10-alkyl-10-hydroxyoctahydrobenzocycloheptapyrans of this invention can be dehydrated toprovide the corresponding 9-alkyl and 10-alkylhexahydrobenzocycloheptapyrans of this invention, compounds having theabove general formula wherein Z is selected from the group consisting of##STR13## in which R⁵ is C₁ -C₄ alkyl.

The dehydration of such 9-alkyl-9-hydroxy or 10-alkyl-10-hydroxyderivatives can be accomplished by reaction with an acid such assulfuric acid or paratoluenesulfonic acid, generally under essentiallyanhydrous conditions since water is being formed during the reaction.The reaction preferably is carried out in a solvent which forms anazeotrope with water, thereby allowing the water to be continuouslyremoved from the reaction mixture by distillation of the azeotrope. Thereaction typically is carried out in benzene in a flask equipped with aDean Stark trap for water removal. Other methods available for removingthe water which is formed as part of the reaction include the use ofmolecular sieves. The dehydration reaction generally is carried out at atemperature of about 40° to 80° C. where the azeotrope boils, and issubstantially complete within about one to ten hours. The product, a9-alkyl or 10-alkyl-hexahydrobenzo[b]cyclohepta[d]pyran, is readilyisolated by removing any excess acid from the reaction mixture, forinstance by washing the mixture with an aqueous base, separating theorganic layer and then evaporating the reaction solvent. Furtherpurification can be accomplished if desired by routine methods such aschromatography.

Hexahydrobenzocycloheptapyrans which are unsubstituted in the C ring,ie. compounds having the above formula wherein R⁵ is hydrogen, can beprepared by dehydration of 9-hydroxy or10-hydroxy-octahydrobenzocycloheptapyrans. Such compounds preferably areprepared, however, by reacting 9-oxo or10-oxo-octahydrobenzocycloheptapyrans with paratoluenesulfonylhydrazineto provide the corresponding tosylhydrazone, which when treated with abase such as sodium in ethylene glycol or lithium diisopropylamide intetrahydrofuran effects elimination of the tosylhydrazone moiety toprovide a hexahydrobenzocycloheptapyran.

The hexahydrobenzocycloheptapyrans of this invention are potentpharmacological agents, and also serve as intermediates in the synthesisof the octahydrobenzocycloheptapyrans of this invention which areunsubstituted at the 9 and 10 positions or are substituted with a C₁ -C₄alkyl group at such positions. For instance, catalytic hydrogenation ofa compound such as(±)-6a,11a-trans-1-hydroxy-3-(1,2-dimethylheptyl)-6,6-dimethyl-9-isopropyl-6,6a,7,8,11,11a-hexaydrobenzo[b]cyclohepta[d]pyranby reaction with hydrogen in the presence of a catalyst such as 5percent palladium on carbon effects hydrogenation of the Δ⁹,10 doublebond to provide(±)-6a,11a-trans-1-hydroxy-3-(1,2-dimethylheptyl)-6,6-dimethyl-9-isopropyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclopheta[d]pyran.

It will be noted that all of the above described synthetic reactions arecarried out on compounds having a 1-hydroxy group, ie. R¹ in the abovegeneral formula is hydrogen. Any of the 1-hydroxy compounds heretoforedescribed can be converted to 1-alkanoyloxy derivatives, wherein R¹ isC₁ -C₄ alkanoyl, by reaction with an acylating agent. For example, a10-oxo derivative such as1-hydroxy-3-isodecyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyrancan be reacted with about an equimolar quantity of an acylating agentsuch as a C₁ -C₄ alkanoic acid halide or anhydride to provide thecorresponding 1-alkanoyloxy-10-oxo derivative. Reduction of suchderivative as hereinabove pointed out provides the corresponding1-alkanoyloxy-10-hydroxy octahydrobenzocycloheptapyran of thisinvention. The 1-alkanoyloxy compounds provided herein are usefulpharmacological agents. When desired, they can be converted to theparent 1-hydroxy derivatives by simple acid or base hydrolysis.

The following list of representative compounds illustrates the scope ofbenzocycloheptapyrans contemplated by this invention. The listing is byno means inclusive of the various compounds comprehended, but is merelya representation.

(±)-6a,11a-trans-1-hydroxy-3-n-hexyl-9-oxo-10-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-hydroxy-3-(1,2,3-trimethylhexyl)-6,6-dimethyl-9-methoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(-)-6a,11a-trans-1-hydroxy-3-(1-methyl-2-heptenyl)-9-isobutoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-trans-1-acetoxy-3-(1,2-dimethyloctyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-formyloxy-3-(2-hexenyl)-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-hydroxy-3-n-octyl-6,6-dimethyl-9-ethyl-9-hydroxy-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(-)-6a,11a-trans-1-hydroxy-3-(1,2-dimethylpentyl)-10R-hydroxy-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-trans-1-isobutyroxy-3-n-heptyl-10α-hydroxy-10β-methyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-hydroxy-3-(1,1-dimethylheptyl)-9-ethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran;

(-)-6a,11a-trans-1-hydroxy-3-(1,2-dimethyl-1-hexenyl)-6,6-dimethyl-9-n-propyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran;

(-)-6a,11a-trans-1-acetoxy-3-(1-ethyl-2-methylhexyl)-6,6-dimethyl-10-isopropyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-propionoxy-3-n-pentyl-6,6,10-trimethyl-6,6a,7,8,9,11a-hexahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-trans-1-hydroxy-3-(1-ethylheptyl)-6,6-dimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran;

(±)-6a,11a-cis-1-acetoxy-3-n-octyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran;and

(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethyloctyl)-6,6-dimethyl-9-ethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran.

All of the octahydro and hexahydrobenzo[b]cyclohepta[d]pyrans providedby this invention are new chemical compounds having a variety of usefulpharmacological activities, and accordingly are useful in treatingdisorders commonly occuring in humans. A further embodiment of thisinvention therefore includes pharmaceutical formulations containing atleast one of the compounds of this invention in association with one ormore pharmaceutically-acceptable diluents, carriers or excipientstherefor. If desired, one or more other pharmacologically active drugscan be incorporated into the formulation containing a compound of thisinvention. The formulations provided by this invention can beadministered to mammals, especially humans, for the treatment or controlof anxiety, depression, glaucoma and pain. A particularly preferredformulation of this invention is one useful in the treatment ofhypertension, and thus comprises a hypotensively effective dose of acompound having the above formula in association with a carriertherefor. Especially preferred formulations useful in the treatment ofhypertension comprise a compound having the above formula wherein R¹ ishydrogen, R² is alkyl, R³ is methyl, and Z is selected from the groupconsisting of ##STR14## wherein R⁵ is hydrogen or methyl and R⁶ ishydrogen or hydroxy, in association with a suitable carrier therefor.

The formulations contemplated by this invention can take on a form whichis readily conducive to the particular route of administration desiredin each particular case. For oral administration, which is preferredaccording to this invention, a compound of this invention is admixedwith carriers and diluents such as dextrose, lactose, mannitol, calciumsilicate, potato starch, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, potassium benzoate, and relatedexcipients. Such formulations can be molded into tablets or enclosed ingelatin capsules. The mixtures can alternatively be dissolved in liquidssuch as ten percent aqueous glucose solution, isotonic saline, sterilewater, or the like, and administered intravenously or by injection. Suchsolutions can, if desired, be lyophilized and stored in a sterileampoule ready for reconstitution by the addition of sterile water forready intramuscular injection.

A particularly preferred formulation useful for treating hypertension inhuman subjects comprises a compound such as(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranor (±)-6a,11a-trans-1-hydroxy-b3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran,or a mixture of such isomers, in the amount of about 100 mcg. to about250 mcg. in combination with a carrier such as sucrose or starch in theamount of about 300 to about 500 mg. Such formulation can be molded intotablets and administered to a subject suffering from high blood pressureat the rate of from about 1 to about 4 tablets per day or as need by theparticular patient.

As already pointed out, the compounds of this invention have a varietyof pharmacological utilities. Most of the compounds have demonstratedactivity in standard tests designed to show analgesic, anti-depressantand anti-anxiety activity, as well as hypotensive activity. The mostpotent compounds provided herein appear to be the hexahydro andoctahydrobenzocycloheptapyrans of the above general formula wherein R⁵is C₁ -C₄ alkyl and R⁶ is hydrogen or hydroxy. Especially preferredcompounds are the 9-alkyl and the10-alkyl-hexahydrobenzocycloheptapyrans, particularly those wherein the9-alkyl or 10-alkyl group is methyl. Even though such compounds arepreferred because of their biological properties, all of the compoundsprovided herein are useful biologically. For example,(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranhad a minimum effective dose (MED) of only 2.5 mg./kg. p.o. whenanalyzed in the standard mouse activity assay. Similarly, when(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranwas tested in the septal lesion rat assay, it demonstrated an MED of 5.0mg./kg. p.o. When(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-10.alpha.-hydroxy-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranwas assayed for analgesic activity in the mouse writhing test, itdemonstrated an ED₅₀ p.o. of only 0.2 mg./kg. When tested for theirability to reduce the blood pressure of rabbits,(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,10β-trimethyl-10α-hydroxy-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranhad an MED of 16 mcg./kg. i.v., while a mixture of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand the 6,6a,7,8,11,11a-hexahydro derivative had an MED of only 2mcg./kg. when administered intravenously.

As can readily be seen from the foregoing discussion of biologicalactivity, the compounds of this invention are useful in the treatment ofhypertension, anxiety, depression, pain, glaucoma and related maladies.The compounds can thus be used to treat animals and humans alikesuffering from one or more of such conditions. A further embodiment ofthis invention is a method of treating hypertension in mammalscomprising administering a hypotensive dose of a hypotensively activecompound of this invention to a subject suffering from hypertension andin need of treatment or to a subject suspected of developinghypertension and in need of prophylactic treatment. An especiallypreferred method of treating hypertension according to this inventioncomprises administering a compound of this invention having the abovegeneral formula wherein R¹ is hydrogen, R² is alkyl, R³ is methyl and Zis selected from the group consisting of ##STR15## wherein R⁵ ishydrogen or methyl and R⁶ is hydrogen or hydroxy.

The hypotensively benzocycloheptapyran derivatives of this invention canbe administered by any of a number of routes, including the oral,subcutaneous, intramuscular and intravenous routes. Typical dosagesuseful for the treatment of humans will of course vary depending uponthe particular hypertension condition being treated, but typically willrange from about 0.1 to about 10 mcg./kg. of subject body weight. Dailydosages commonly utilized when treating hypertension, for example, willrange from about 1 to about 500 mcg. for a patient weighing about 50 toabout 75 kg. A commonly used dose will be in the amount of about 50 mcg.to about 100 mcg.

The preparation of the benzocycloheptapyran compounds comprehended bythis invention is more fully described in the following examples. It isof course to be understood, however, that the examples are illustrativeof the compounds embraced by the invention and of methods commonlyemployed in their preparation and are not to be construed as limitingthe invention to any of the particular compounds or methods specificallydescribed.

EXAMPLE 1(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10.alpha.-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

A solution of 12.97 g. of(±)-6a,10a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrodibenzo[b,d]pyran-9-onein 175 ml. of dichloromethane was stirred under nitrogen and cooled inan ice bath. To the cold reaction mixture was added 14 g. oftriethyloxonium tetrafluoroborate followed by the addition of 7.7 ml. ofethyldiazoacetate. The reaction mixture then was stirred at about 5° C.for one hour and then diluted with 250 ml. of 5 percent aqueous sodiumbicarbonate solution. The organic layer was separated and the aqueouslayer was extracted with fresh dichloromethane. The organic layers werecombined, dried and the solvent was removed therefrom by evaporationunder reduced pressure to provide 16.2 g. of the product as a red oil.The oil thus formed was applied to the chromatographic column packedwith silica gel and the column was eluted with 2 percent ethyl acetatein dichloromethane. The fractions shown by thin layer chromatographicanalysis to contain the desired product were combined and the solventwas removed therefrom by evaporation under reduced pressure thusaffording 5.36 g. of the desired product as a clear oil. The clear oilwas crystallized from hexane and dichloromethane to afford(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10α-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 101°-102° C.

IR (CHCl₃): 5.78μ (C═O ester); 5.86μ (C═O ketone), H¹ NMR (CDCl₃): δ7.82 (s, 1H); δ 4.34 (q, 2H); δ 1.34 (t, 3H); mass spec. m/e 458 (M⁺);

Analysis Calc. For C₂₈ H₄₂ O₅ -- Theory: C, 73.33; H, 9.23. Found: C,73.10; H, 9.44.

EXAMPLE 2(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

Further chromatographic separation of the crude product obtained asdescribed in Example 1 provided fractions containing the desiredcompound as demonstrated by thin layer chromatographic analysis. Theappropriate fractions were combined and the solvent was removedtherefrom by evaporation under reduced pressure to provide 2.74 g. ofthe desired product as a light yellow oil. The oil thus formed wascrystallized from hexane to provide(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 121°-124° C.

IR (CHCl₃): 5.67μ (C═O ester); 5.90μ (C═O ketone); H¹ NMR (CDCl₃): δ4.22(q, 2H); δ 1.26 (t, 3H); mass spec. m/e 458 (M⁺);

Analysis Calc. for C₂₈ H₄₂ O₅ -- Theory: C, 73.33; H, 9.23; O, 17.44.Found: C, 73.07; H, 9.05; O, 17.34.

EXAMPLE 3(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10.beta.-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[d]cyclohepta[d]pyran

A solution of 1.0 g. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10α-ethoxycarbonyl-6,6a,7,8,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin 25 ml. of pyridine was stored at 25° C. for 48 hours. The reactionmixture was diluted with water and with 100 ml. of ethyl acetate and theaqueous mixture then was washed twice with 200 ml. portions of 1 Nhydrochloric acid, once with 100 ml. of water, and once with 50 ml. ofbrine solution. The remaining organic layer was dried and the solventwas removed by evaporation under reduced pressure to provide 900 mg. ofthe product as a yellow oil. The oil thus formed was crystallized fromhexane to provide(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10β-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 96°-98.5° C.

IR (CHCl₃): 5.78μ (C═O ester); 5,86μ (C═O ketone); H¹ NMR (CDCl₃): δ4.95 (s, 1H); δ 1.23 (t, 3H); mass spec. m/e 458 (M⁺);

Analysis Calc for C₂₈ H₄₂ O₅ -- Theory: C, 73.33; H, 9.23. Found: C,73.59; H, 9.29.

EXAMPLE 4(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

A solution of 6.0 g. of a mixture containing(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-10α-ethoxycarbonyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranand the corresponding 10β-ethoxycarbonyl derivative dissolved in 800 ml.of acetic acid containing 320 ml. of concentrated hydrochloric acid and100 ml. of water was stirred and heated at reflux for 2 hours. Thereaction mixture then was cooled to room temperature and diluted with 1liter of water. The aqueous reaction mixture was extracted three timeswith 200 ml. portions of dichloromethane. The organic extracts werecombined, washed with water, with 5 percent sodium bicarbonate solution,with brine, and dried. Removal of the solvent by evaporation underreduced pressure afforded 4.8 g. of a greenish oil. The oil thus formedwas applied to a chromatographic column packed with silica gel andeluted with 3 percent ethyl acetate and benzene. Fractions shown by thinlayer chromatographic analysis to contain a single product were combinedand the solvent was removed therefrom by evaporation to afford 2 g. of aclear oil. The oil was crystallized from hexane to provide(+)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranas white crystals, m.p. 102.5°-104.5° C.

IR (CHCl₃): 5.90μ (C═O); H¹ NMR (CDCl₃); δ 5.35 (s, 1H); δ 1.17 (s, 6H);δ 0.80 (t, 3H); mass spec. m/e 386 (M⁺);

Analysis Calc. for C₂₅ H₃₈ O₃ -- Theory: C, 77.68; H, 9.91. Found: C,77.62; H, 9.88.

EXAMPLE 5(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

Following the general procedure set forth in Example 4, a solution of3.3 g. of(±)-6a,11-a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-ethoxycarbonyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin acetic acid, water and concentrated hydrochloric acid was heated toreflux and stirred for 2 hours. The product was isolated and purified bychromatography and crystallization from methylcyclopropane anddichloromethane to afford(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranas white crystals, m.p. 81.5°-83.5° C.

IR (CHCl₃): 5.95μ (C═O); H¹ NMR (CDCl₃): δ 5.92 (s, 1H); δ 1.17 (s, 6H);δ 0.82 (t, 3H); mass spec. m/e 386 (M⁺);

Analysis Calc. for C₂₅ H₃₈ O₃ -- Theory: C, 77.68; H, 9.91. Found: C,77.56; H, 10.18.

EXAMPLE 6(±)-6a,11a-trans-1,9α-Dihydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

A solution of 1.005 g. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyrandissolved in 50 ml. of ethyl alcohol was added in one portion to astirred suspension of 0.6 g. of sodium borohydride in 30 ml. of ethylalcohol. The reaction mixture was stirred at room temperature for 12hours and then added to 125 ml. of a cold solution of 0.1 N hydrochloricacid. The organic layer was then separated and the aqueous layer wasextracted with diethyl ether. The organic layers were combined, washedwith water, and dried. Removal of the solvent by evaporation underreduced pressure provided a white foam. The foam thus formed was appliedto a chromatographic column packed with silica gel and eluted with 5percent acetonitrile and dichloromethane. The fraction shown by thinlayer chromatographic analysis to contain the major component werecombined and the solvent was removed therefrom by evaporation to providethe product as a white foam. The product was shown in consist of amixture of (±)-6a,11a-trans-1,9α-dihydroxy-(and1,9β-dihydroxy)-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran.

UV (CH₃ OH) λ_(max) ]08 (ε=43860); mass spec. m/e 388 (M⁺);

Analysis Calc. for C₂₅ H₄₀ O₃ -- Theory: C, 77.27; H, 10.38. Found: C,77.18; H, 10.15.

EXAMPLE 7(±)-6a,11a-trans-1,10α-Dihydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

Following the same general procedure set forth in Example 6, a solutionof 1.335 g. of(±)-6a,10a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin 75 ml. of ethyl alcohol was reduced by reaction with 800 mg. ofsodium borohydride in 35 ml. of ethyl alcohol. The product was isolatedas described in Example 6 to provide 1.242 g. of a crude oil.Chromatography of the oil so formed over a column packed with silicagel, eluting with 2 percent acetonitrile and dichloromethane, afforded468 mg. of an oil which when crystallized from hexane gave whitecrystalline(+)-6a,11a-trans-1,10α-dihydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 109°-110° C.

UV (CH₃ OH): λ_(max) 209, 273 (ε=52217; 1124); H¹ NMR (CDCl₃): δ 7.26(s, 1H); δ 2.60 (s, 1H); δ 1.20 (s, 6H); δ 0.83 (t, 3H); mass spec. m/e388 (M⁺);

Analysis Calc. for C₂₅ H₄₀ O₃ -- Theory: C, 77.27; H, 10.38. Found: C,77.09; H, 10.28.

EXAMPLE 8

Further chromatographic separation of the crude product prepared inExample 7 afforded fractions which when combined and concentrated todryness under reduced pressure gave 1.013 g. of an oil. The oil wascrystallized from hexane to afford white crystalline(±)-6a,11a-trans-1,10β-dihydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 146.5°-147.5° C.

UV (CH₃ OH): λ_(max) 208,273 (ε=50016; 1091); H¹ NMR (CDCl₃): δ 6.12 (s,1H); δ 1.18 (s, 6H); δ 0.83 (t, 3H); mass spec. m/e 388 (M⁺);

Analysis Calc. for C₂₅ H₄₀ O₃ -- Theory: C, 77.26; H, 10.38. Found: C,77.20; H, 10.41.

EXAMPLE 9(±)-6a,11a-trans-1,10α-Dihydroxy-3-(1,1-dimethylheptyl)-6,6,10.beta.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

A solution of 1.051 g. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-10-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin 40 ml. of dry diethyl ether was added dropwise over 10 minutes to astirred refluxing solution of 10 ml. of 3 molar methyl magnesium bromidein 10 ml. of dry diethyl ether. Following complete addition, thereaction mixture was stirred and heated at reflux for 18 hours and thencooled to room temperature and diluted with 100 ml. of 0.1 Nhydrochloric acid solution which had been chilled to 0° C. in an icebath. The acidity of the reaction mixture was adjusted to pH 5 by thedropwise addition of 1 N hydrochloric acid. The organic layer then wasseparated and the aqueous layer was extracted with 50 ml. of freshdiethyl ether. The organic portions then were combined and washed twicewith 100 ml. portions of water, once with a 50 ml. portion of brine, anddried. Removal of the solvent by evaporation under reduced pressureafforded 804 mg. of a white foam. The foam was applied to achromatographic column packed with silica gel and eluted with a gradientsolvent starting at 2 percent acetonitrile in dichloromethane and endingwith 3 percent acetonitrile in dichloromethane. Fractions shown by thinlayer chromatographic analysis to contain one componet were combined andthe solvent was removed therefrom by evaporation under reduced pressureto afford 649 mg. of a white foam. The foam was crystallized from hexaneto afford(±)-6a,11a-trans-1,10α-dihydroxy-3-(1,1-dimethylheptyl)-6,6,10.beta.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 113°-115° C.

UV (CH₃ OH) λ_(max) 208 (ε=50187); H¹ NMR (CDCl₃): δ 1.20 (s, 6H); δ0.83 (t, 3H); mass spec. m/e 402 (M⁺);

Analysis Calc. for C₂₆ H₄₂ O₃ -- Theory: C, 77.56; H, 10.52. Found: C,77.62; H, 10.33.

EXAMPLE 10

Further chromatographic separation of the crude product obtained asdescribed in Example 9 provided fractions which were shown by thin layerchromatographic analysis to contain a single component which wasdifferent than the product of Example 9. Such fractions were combinedand the solvent was removed therefrom to provide 56 mg. (±)dl-6a,11a-trans-1,10β-dihydroxy-3-(1,1-dimethylheptyl)-6,6,10α-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranas a white solid.

H¹ NMR (CDCl₃): δ 4.95 (s, 1H); δ 1.19 (s, 6H); δ 0.83 (t, 3H); massspec. Calc. for C₂₆ H₄₂ O₃ 402.31338; found 402.31316.

EXAMPLES 11-12

(±)-6a,11a-trans-1,9α-Dihydroxy-3-(1,1-dimethylheptyl)-6,6,9β-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1,9β-dihydroxy-3-(1,1-dimethylheptyl)-6,6,9.alpha.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran

To a stirred refluxing solution of 9.7 ml. of a three molar solution ofmethyl magnesium bromide in 20 ml. of diethyl ether was added over 10minutes a solution of 957 mg. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin 40 ml. of diethyl ether. The reaction mixture was stirred and heatedat reflux for 12 hours and then cooled to room temperature and pouredinto 50 ml. of ice water. One normal hydrochloric acid solution wasadded to the cold aqueous reaction mixture to adjust the pH of thesolution to 7. The organic layer then was separated and the aqueouslayer was extracted with 50 ml. of fresh diethyl ether. The organicphases were combined, washed once with 100 ml. of water and once with 50ml. of brine and dried. Evaporation of the solvent under reducedpressure provided 943 mg. of a clear oil. The oil thus formed wascrystallized from acetonitrile and dichloromethane to provide as a whitecrystalline product(±)-6a,11a-trans-1,9α-dihydroxy-3-(1,1-dimethylheptyl)-6,6,9.beta.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran,m.p. 155.5°-157° C.

UV (CH₃ OH) λ_(max) 209 (ε=44012); H¹ NMR (CDCl₃): δ 4.91 (s, 1H); δ1.17 (s, 6H); δ 0.82 (t, 3H); mass spec. m/e 402 (M⁺);

Analysis Calc. for C₂₆ H₄₂ O₃ -- Theory: C, 77.56; H, 10.52. Found: C,77.29; H, 10.28.

The filtrate from the above-described crystallization was concentratedto dryness by evaporation of the solvent under reduced pressure and theresidue thus formed was applied to a chromatographic column packed withsilica gel and eluted with a 5 percent solution of methanol indichloromethane. Fractions shown by thin layer chromatography to containone component were combined and the solvent was removed therefrom byevaporation to provide 50 mg. of a white solid which was shown to be(±)-6a,11a-trans-1,9β-dihydroxy-3-(1,1-dimethylheptyl)-6,6,9.alpha.trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran.

UV (CH₃ OH) λ_(max) 209 (ε=44012); H¹ NMR (CDCl₃): δ 6.04 (s, 1H); δ1.18 (s, 6H); δ 0.84 (t, 3H);

Mass spec. Calc. for C₂₆ H₄₂ O₃ -- Theory: 402.31338. Found: 402.31316.

EXAMPLE 13(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran

A solution containing 100 mg. of a 50:50 mixture of(±)-6a,11a-trans-1,9α-dihydroxy-3-(1,1-dimethylheptyl)-6,6,9.beta.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranand the corresponding 9β-hydroxy-9α-methyl compound dissolved in 100 ml.of benzene containing 100 mg. of p-toluenesulfonic acid was stirred andheated at reflux in a flask equipped with a Dean Stark trap for waterremoval. The reaction mixture was heated at reflux for 1 hour and thencooled to room temperature and washed twice with 50 ml. portions ofwater, once with 25 ml. of 5 percent aqueous sodium bicarbonate, andonce with 25 ml. of brine. The organic layer was separated and dried,and the solvent was removed therefrom by evaporation under reducedpressure to provide the crude product as a brownish oil. The oil waspurified by chromatography over a column packed with fluorosil andeluted with a 2 percent solution of diethyl ether in petroleum ether.Fractions shown by thin layer chromatographic analysis to contain themajor component were combined and the solvent was removed to provide amixture of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand the corresponding6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran.

H¹ NMR (CDCl₃): δ4.9 (s, 1H); δ1.7 (s, 3H);

mass spec. Calc. for C₂₆ H₄₀ O₂ -- Theory: 384.30281. Found: 384.30181.

EXAMPLE 14(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6,10-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,10-trimethyl-6,6a,7,8,9,11a-hexahydrobenzo[b]cyclohepta[d]pyran

Following the general procedure set forth in Example 13, 500 mg. of amixture of(±)-6a,11a-trans-1,10α-dihydroxy-3-(1,1-dimethylheptyl)-6,6,10.beta.-trimethyl-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranand the corresponding 10β-hydroxy-10α-methyl compound was reacted with50 mg. of p-toluenesulfonic acid in 75 ml. of benzene. The reactionmixture was worked up in the normal fashion and the crude product waspurified by chromatography over fluorosil, eluting with 2 percentdiethyl ether in petroleum ether. The appropriate fractions werecombined and concentrated to dryness to afford a product identified as amixture of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,10-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand the corresponding6,6a,7,8,9,11a-hexahydrobenzo[b]cyclohepta[d]pyran.

H¹ NMR (CDCl₃): δ4.9 (s, 1H); δ2.4 (s, 3H); Mass spec. Calc. for C₂₆ H₄₀O₂ -- Theory: 384.30281. Found: 384.30234.

EXAMPLE 15(±)-6a,11a-trans-1-Hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran

A solution of 707 mg. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-oxo-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyranin 25 ml. of methanol containing 341 mg. ofpara-toluenesulfonylhydrazide was stirred at room temperature for 4hours. Removal of the solvent by evaporation under reduced pressureprovided 1.05 g. of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(p-toluenesulfonylhydrazino)-6,6a,7,8,9,10,11,11a-octahydrobenzo[b]cyclohepta[d]pyran.A solution of the latter compound in 50 ml. of tetrahydrofuran was addeddropwise over thirty minutes to a cold stirred solution of 0.77 ml. ofdiisopropylamine in 10 ml. of tetrahydrofuran containing 3.43 ml. of a1.0 molar solution of n-butyl lithium in hexane. Following completeaddition, the reaction mixture was warmed to room temperature andstirred for three hours. The reaction mixture next was diluted by theaddition of 20 g. of ice and it was then poured into 100 ml. of fiftypercent diethyl ether in water. The ethereal layer was separated, washedwith water and with brine, and dried. Removal of the solvent byevaporation under reduced pressure provided 500 mg. of an oil. The oilwas purified by high pressure liquid chromatography, eluting withdichloromethane, to afford 306 mg. of(±)-6a,10a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand the corresponding Δ⁹,10 -isomer.

Mass spec. Calc. for C₂₅ H₃₈ O₂ -- Theory: 370.28668. Found: 370.287.

EXAMPLE 16

A formulation suitable for the treatment of hypertension according tothis invention may have the following composition:

    ______________________________________                                        (±)-trans-1-hydroxy-3-(1,1-dimethyl                                                               50 mcg.                                                heptyl)-6,6,9-trimethyl-6,6a,7,10,11,                                         11a-hexahydrobenzo[b]cyclohepta[d]pyran                                       (±)-trans-1-hydroxy-3-(1,1-dimethyl-                                                              50 mcg.                                                heptyl)-6,6,9-trimethyl-6,6a,7,8,11-                                          11a-hexahydrobenzo[b]cyclohepta[d]pyran                                       polyoxyethylenesorbitan monooleate                                                                   50 mcg.                                                starch powder          250 mg.                                                ______________________________________                                    

The above ingredients should be thoroughly mixed and can be placed in anempty gelatin capsule. Such capsules may be administered orally to ahuman from 1 to about 4 times a day for the control of high bloodpressure.

We claim:
 1. A pharmaceutical formulation useful for treatinghypertension which comprises a hypotensively effective amount of acompound of the formula ##STR16## wherein: R¹ is hydrogen or C₁ -C₄alkanoyl;R² is C₅ -C₁₀ alkyl or C₅ -C₁₀ alkenyl; R³ is hydrogen ormethyl; and Z is selected from the group consisting of ##STR17##wherein: R⁴ is hydrogen or C₁ -C₄ alkoxycarbonyl; R⁵ is hydrogen or C₁-C₄ alkyl; and R⁶ is hydrogen or hydroxy, in combination with apharmaceutically acceptable carrier therefor.
 2. The formulationaccording to claim 1 wherein in the formula defining the activeingredient,R¹ is hydrogen, R² is C₅ -C₁₀ alkyl, R³ is methyl, and Z isselected from the group consisting of ##STR18## wherein: R⁵ is hydrogenor C₁ -C₄ alkyl; and R⁶ is hydrogen or hydroxy.
 3. The formulationaccording to claim 2 wherein R⁵ is hydrogen or methyl.
 4. Theformulation according to claim 3 wherein the active ingredient is amixture of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran.5. A method of treating hypertension comprising administering to asubject suffering from hypertension and in need of treatment or to asubject suspected of developing hypertension a hypotensively effectivedose of a compound of the formula ##STR19## wherein: R¹ is hydrogen orC₁ -C₄ alkanoyl;R² is C₅ -C₁₀ alkyl or C₅ -C₁₀ alkenyl; R³ is hydrogenor methyl; and Z is selected from the group consisting of ##STR20##wherein: R⁴ is hydrogen or C₁ -C₄ alkoxycarbonyl; R⁵ is hydrogen or C₁-C₄ alkyl; and R⁶ is hydrogen or hydroxy.
 6. The method according toclaim 5 wherein in the compound administered,R¹ is hydrogen, R² isalkyl, R³ is methyl, and Z is selected from the group consisting of##STR21## wherein: R⁵ is hydrogen or C₁ -C₄ alkyl; and R⁶ is hydrogen orhydroxy.
 7. The method according to claim 6 wherein R⁵ is hydrogen. 8.The method according to claim 6 wherein R⁵ is C₁ -C₄ alkyl.
 9. Themethod according to claim 8 wherein R⁵ is methyl.
 10. The methodaccording to claim 9 wherein in the compound administered, Z is##STR22##
 11. The method according to claim 10 wherein the compoundadministered is selected from the group consisting of(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,10,11,11a-hexahydrobenzo[b]cyclohepta[d]pyranand(±)-6a,11a-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6,6a,7,8,11,11a-hexahydrobenzo[b]cyclohepta[d]pyran.